Platelets in Cardiovascular Biology and Pathology

Massachusetts Institute Of Technology, Cambridge MA

Investigators

Linked publications & trials

Abstract

It is becoming evident that the importance of platelets in animal physiology far exceeds their role in vascular[unreadable] injury. In this proposal, we will address platelet function in angiogenesis, inflammation and heart disease. In[unreadable] addition, we will investigate the role of the metalloproteinase ADAMTS-13 and the effect of elevated procoagulant[unreadable] activity on vascular function, in particular in the brain. The project will be divided into three[unreadable] independent but thematically related Specific Aims.[unreadable] The first specific aim will develop our preliminary observations that platelets play an important role in[unreadable] angiogenesis by preventing hemorrhage. In collaboration with Project V (Hynes), we will test the hypothesis[unreadable] that platelet adhesion through adhesion receptors is required for angiogenesis. We will visualize platelet[unreadable] interactions with angiogenic vessels by multiphoton microscopy and study angiogenesis in mice mutant in[unreadable] various adhesion molecules. The role of platelet secretion in vessel stabilization will also be addressed.[unreadable] The second specific aim will study the pro-inflammatory functions of platelets and, with Project I (Krieger), the[unreadable] role of platelets in severe heart disease and atherosclerosis. We have observed that the presence of activated[unreadable] platelets in circulation, such as may occur in surgical patients, systemically activates endothelium and[unreadable] increases P-selectin expression. This is reflected in enhanced leukocyte rolling on the vessel wall. The[unreadable] molecular mechanisms of this new inflammatory platelet function will be explored. Knowing the role of platelets[unreadable] in inflammation, we were surprised to observe that in advanced heart disease, such as seen in the mouse[unreadable] models developed in Project I, platelet function had a protective effect on the animals. We hypothesize that[unreadable] platelets are crucial to prevent hemorrhage in the diseased heart, thus preventing excessive fibrosis of the[unreadable] organ. Fibrin deposition in the lesions was drastically reduced in the absence of platelets, indicating that[unreadable] platelets may be required for localized coagulation to occur. We will address this experimentally.[unreadable] The last aim will examine the consequences of pro-coagulant and pro-thrombotic conditions on blood vessel[unreadable] function. We have preliminary results that indicate that high levels of pro-coagulant microparticles in an[unreadable] animal's plasma lead to a breakdown of the endothelial blood-brain barrier. We hypothesize that this involves[unreadable] excessive thrombin generation/fibrin deposition resulting in signaling leading to vascular permeability. The[unreadable] proposed molecular mechanism will be studied. We have also begun analysis of mice lacking ADAMTS-13, a[unreadable] mouse model of thrombotic thrombocytopenic purpura (TTP). We will evaluate the role of this enzyme in[unreadable] platelet adhesion to endothelium and in thrombotic models.[unreadable] Project II will further collaborate with Project III (Lodish) on the role of adiponectin and T-cadherin in[unreadable] thrombosis and atherosclerosis.